Po-259 identification of a clinically meaningful site-specific steroid roadmap in prostate cancer.

Introduction In prostate cancer the genotype of the tumour does not always predict clinical behaviour and disease aggressiveness after castration therapy. Additional factors might be important. Here we hypothesise that there is a site-specific steroid profile roadmap after castration that is of clinical significance. Material and methods Steroid profiles in blood plasma (BP) and bone marrow aspirate plasma (BMA) from 120 castrated patients with prostate cancer were evaluated with mass spectrometry. We studied the steroid ligand-receptor interactions in prostate cancer adrenal metastases (PCAM) because they represent a steroid-rich environment. Adrenalectomy specimens from 3 castrated patients with PCAM were analysed. Results and discussions It is known that normally BP/Adrenal vein plasma testosterone (T) concentration ratio is approximately 1:1 and cortisol (C) ratio is roughly1:3. We measured similar T levels in BP and BMA. The levels of C were significantly lower in BMA compared to BP. Our data suggest that T levels are uniform but there is a C concentration gradient between the different compartments. Cortisol acts through GR and in the presence of T is a partial AR inhibitor. All PCAM samples had functional androgen receptor (AR) (wild-type (wt), no copy number changes) and glucocorticoid (GR), but no progesterone receptor (PR). No DHT was detected. Patient 1 tumour was able to synthesise T and had above castrate intra-tumoral T levels. The tumour lacked enzymes to synthesise, but was able to catabolize C. The levels of C were within the normal BP range. Gene expression of AR was normal. Patient 2 and 3 samples had castrate T and high C levels (3-fold BP), but AR gene expression was remarkably high. All patients had PTEN and RB deletions, while patients 2 and 3 had mutant (m) p53. Addition of 40 ng/dl T increased growth in vitro in a xenograft PCAM model (propagated in matrigel) derived from patient 1. When C was concomitantly added at high levels such as those in patients 2 and 3, PCAM growth returned to baseline (no steroids), suggesting that almost all T or C activity were lost. Moreover, proliferation in VCAP cells (High AR/GR+) decreased when high C was added in low T, but remained well above baseline, generating the hypothesis that this steroid combination mostly inhibits AR/GR tumours with non-amplified AR (e.g. early in castration). Conclusion There is a clinically meaningful site-specific steroid roadmap. The PCAM steroid profile may serve as a useful model to elucidate tumour interactions with the steroid environment.